Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

Cardellina, John H.; Roxas-Duncan, Virginia; Montgomery, Vicki A.; Eccard, Vanessa S.; Campbell, Yvette; Hu, Xin; Khavrutskii, Ilja V.; Tawa, Gregory J.; Wallqvist, Anders; Gloer, James B.; Phatak, Nisarga L.; Höller, Ulrich; Soman, Ashish G.; Joshi, Biren K.; Hein, Sara M.; Wicklow, Donald T.; Smith, Leonard A.

doi:10.1021/ml200312s

Cited by 23 publications

(13 citation statements)

References 38 publications

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“…The structures of compounds 1 – 8 were determined by 1 H NMR, 13 C NMR, MS, and ECD data analysis and by comparison with the literature 16 17 18 19 20 . Compounds of this type usually display axial chirality due to the high energy barrier for rotation of the bond linking the individual aromatic systems 19 21 . According to the literature 22 23 , ( R )-configured dimeric naphtho- γ -pyrones exhibit a negative Cotton effect in the long-wavelength region and a positive one at shorter wavelengths.…”

Section: Resultsmentioning

confidence: 99%

Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens

Tian

Chen

et al. 2016

Sci Rep

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Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1–8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1–8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens.

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Section: Resultsmentioning

confidence: 99%

Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens

Tian

Chen

et al. 2016

Sci Rep

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“…In addition to the cytotoxic, antitumor and antimicrobial activities of bis-nathphtho-γ-pyrones mentioned above, other biological activities include tyrosine kinase inhibition [23], HIV-1 integrase inhibition [3], calmodulin-sensitive cycle nucleotide phosphodiestease inhibition [22], triacylglycerol synthesis inhibition [14], xanthine oxidase inhibition [31], acyl-CoA:cholesterol acyltransferase inhibition [4], central nerveous system depressant effects [42], immunological activity [12], botulinum neutotoxin serotype A inhibition [57], drug resistance-reversing activity [58], and Taq DNA polymerase inhibition [30], which are outlined in Table 5. Anti-tubercular activity [7] …”

Section: Other Biological Activitiesmentioning

confidence: 99%

Bis-naphtho-γ-pyrones from Fungi and Their Bioactivities

Tian

Sun

et al. 2014

Molecules

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Bis-naphtho-γ-pyrones are an important group of aromatic polyketides derived from fungi. They have a variety of biological activities including cytotoxic, antitumor, antimicrobial, tyrosine kinase and HIV-1 integrase inhibition properties, demonstrating their potential applications in medicine and agriculture. At least 59 bis-naphtho-γ-pyrones from fungi have been reported in the past few decades. This mini-review aims to briefly summarize their occurrence, biosynthesis, and structure, as well as their biological activities. Some considerations regarding to synthesis, production, and medicinal and agricultural applications of bis-naphtho-γ-pyrones are also discussed.

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“…19 In general, the most potent BoNT/A LC inhibitors reported to date possess K i values ranging from 0.1 to 10 μM and include hydroxamic acid based compounds 1 and 3 , 20 2,5-diphenylthiophene derivative 2 , 21 betulin derivative 4 , 22 naphthopyrone 5 , 23 and chrysene 6 (24) (Chart 1). …”

Section: Introductionmentioning

confidence: 99%

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

et al. 2014

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Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 μM). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the Ki of compound 67 is 0.10 μM). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds’ in vitro potencies. In addition to specific residue contacts, coordination of the enzyme’s catalytic zinc and expulsion of the enzyme’s catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.

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Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

Cited by 23 publications

References 38 publications

Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens

Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens

Bis-naphtho-γ-pyrones from Fungi and Their Bioactivities

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

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